chr9-124482837-T-C

Position:

• chr9-124482837-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_004959.5(NR5A1):​c.1307A>G​(p.Tyr436Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: NR5A1 NM_004959.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.93

Genes affected

NR5A1 (HGNC:7983): (nuclear receptor subfamily 5 group A member 1) The protein encoded by this gene is a transcriptional activator involved in sex determination. The encoded protein binds DNA as a monomer. Defects in this gene are a cause of XY sex reversal with or without adrenal failure as well as adrenocortical insufficiency without ovarian defect. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a mutagenesis_site Loss of transactivation; when associated with A-440. (size 0) in uniprot entity STF1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR5A1	NM_004959.5	c.1307A>G	p.Tyr436Cys	missense_variant	7/7	ENST00000373588.9	NP_004950.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR5A1	ENST00000373588.9	c.1307A>G	p.Tyr436Cys	missense_variant	7/7	1	NM_004959.5	ENSP00000362690	P1
NR5A1	ENST00000620110.4	c.1187A>G	p.Tyr396Cys	missense_variant	6/6	5		ENSP00000483309
NR5A1	ENST00000373587.3	c.659A>G	p.Tyr220Cys	missense_variant	5/5	3		ENSP00000362689

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Oligosynaptic infertility;C2751824:46,XY disorder of sex development Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 29, 2019

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with NR5A1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with cysteine at codon 436 of the NR5A1 protein (p.Tyr436Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;D;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	.;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.8	.;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	.;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.74
MutPred		0.64		.;Loss of ubiquitination at K440 (P = 0.0464);.;
MVP		0.92
MPC		2.0
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.96
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1832149850; hg19: chr9-127245116; COSMIC: COSV65295287; COSMIC: COSV65295287;